Vertigo & Hearing Loss: A Breakthrough Cure?

0:00Band-Dool is now available everywhere in the U.S. So you can get in on the sports action no matter where you are, including these places. May this year most rewarding season ever with Band-Dool. Agent location restrictions apply. Product availability varies by market. C-FanDool.com for eligibility. Gambling problem called 1-800-Gemma. Hey, this is Tray. Thank you for joining us for a Tuesday edition of our podcast. Our guest today is an expert, a subject matter expert in hearing loss,

1:01which leads to other maladies and can include what we call not we, because I'm not a medical doctor, what others call vestipular disorders. So if you are dizzy, if you know someone who is, if you have ever suffered from vertigo and I'll give you a head, there's more than one kind of vertigo. If you're worried about your hearing now or in the future about your sense of perception or balance, then I have the perfect guest and Dr. Jonathan Kyl, who is also the CEO of Sound Pharmaceutical, which may well have the most exciting new drug in the realm of hearing loss. In decades, if not forever, he is an auto-rino-laryngologist, which I think I did some extra credit for knowing how to pronounce that. We just call it E&T because most of us don't want to say auto-rino-laryngologist.

2:04Dr. Kyl, welcome. Well, thank you. Thank you, Tray. In there are a subset of auto-rino-laryngology that I can't pronounce it, but those that specialize in vestipular disorders, in there are a subset even within E&T. Yes, E&T, auto-laryngology, or as our Europeans say, auto-rino-laryngology, which is probably more correct, has eight fellowships. One requires two additional years of training and a second board. Many of these autology neuro-autologists are double-bored in auto-laryngology and then autology neuro-autology. There are only 26 spots in the country, or I should say, sites that provide this level of additional boarded fellowship,

3:07and each of them accept one to two people a year. So imagine being an MD-PhD for many years, and I have met some MD-PhDs that trained for not just six, seven years, but eight, nine, or ten years, then did an auto-laryngology residency for five to seven years, and then an additional two years. So they didn't get their first jobs until they were 37, 38, 39. On top of pre-med, on top of, you know, all the extra work. And they also made better grades than I made, because there's no way in the world that you can go to school that long and score what I scored on the SAT. All right, let's start with hearing loss. It's more than just not being able to hear your spouse tell you, something, or cranking up the volume too high on your phone.

4:07I think it's also associated with dementia, and other cognitive issues. I mean, people should treat hearing loss in general seriously. Yes, that's gotten a lot of attention over the last ten years. There's a Landsack Commission for studying dementia risk, and they were one of the first to say, hearing loss is the most significant environmental or acquired risk factor beyond your genetics for developing dementia, and it still remains number one. It's more commonly associated with dementia risk than traumatic brain injury and depression, which surprised me. So, you know, it makes sense for me, you know, a neuroscience neurologic point of view, if your brain receives less sensory input because you have hearing loss, or has a problem with discriminating auditory signals like speech,

5:13then yes, your recall, your memory will be affected, and like a muscle, your brain could atrophy, or those areas could atrophy from a lack of activity. So, it makes sense, but it's now nice to see people globally paying attention to this. We've even had some patients on our trials claim that one of the driving factors for them to get fitted for hearing aids was seeing the dementia of an older parent, an uncle, an aunt, and realizing, we may have a risk factor here through genetics, and if improving my sensory input, my auditory processing can stave that off, or potentially decrease the risk of developing dementia, then it's worth it. It was interesting to see that part of the medical equation

6:13drive them to get fitted for hearing aids. So, they already knew they had a hearing problem. They already knew they could benefit from a hearing aid, at least that's what their audiologist was telling them. But what drove them to get finally fitted for hearing aid was this dementia risk. I had never heard the word vestipular until about three or four years ago. Could be because I hang around the wrong people and that my friends aren't that well educated, or it could be that other people have not heard the word vestipular. What is our vestipular system and what is a vestipular disorder? So, the vestibular system is part of the inner ear, so we have an auditory component, the cochlea, which processes sound. The vestibular sensory organs are very complex. There's not just one. You actually have five sensory organs that compose the peripheral vestibular system.

7:14They do have hair cells, like the cochlea does, but they look different. And they are fluid filled, like the cochlea, but the structure is exquisite. Many people have heard of their semi-circular canals, and we have three. They probably never heard of anodolithic organ. These are two of your sensory organs that they contribute to maniaire's disease and vertigo, and they are quite exquisite, quite evolutionarily sophisticated, and they degenerate too. So we think infections, trauma, aging, contribute to some sensory loss, sensory dysfunction in your vestibular sensory organs and the periphery. And that results in degeneration in areas of the brain.

8:16So, your cranial nerve, your vestibular cochlear nerve, projects into the brainstem and through these ascending systems, and allows you to have the sense of balance. So, one of the first things people report as they get older, even if they didn't have infections or trauma or odotoxic drugs, that have these balanced side effects is, I feel less steady. And it's not because of a cardiovascular reason, like they were volume depleted, dehydrated, or even a stroke. They just say, I feel less steady now, especially when I get up where I tilt my head in a certain way. Vertigo is a part of the dizziness spectrum. And many people feel spinning, not just unsteadiness, not just a sense of falling, but literally like I'm spinning on a merry-go-round

9:16and in a bad way, or the room is spinning around me and at an angle. When having now experienced severe vertigo, at the very end of May, twice with subsequent dizziness, it pretty much incapacitated me for about nine hours. And the following day, I was kind of wiped out, but that's all I experienced, other than sweating, nausea, and vomiting. I didn't have hearing loss. I didn't have ringing in the ears or tinnitus. I was rather isolated. And I could sense it coming on within seconds. It started off as this unsteadiness, like I'm going to fall. And then when I sat down to prepare for it, that's when the spinning started.

10:16And I was like, oh, oh. And then trying to keep your eyes open, so we often tell people with motion sickness. Stir it. Keep your eyes open. Don't put your head down in your lap. When you try to keep your eyes open, when you're undergoing a severe vertigo attack, oh, no. Good luck. You have to close your eyes. Yes. And you have to make sure you're lying down because you could literally fall down at each your head. And some patients with the earliest signs of manniars disease had drop attacks. You know, they were often healthy people without, you know, care in the world. And in their 30s, sometimes in their 40s, severe vertigo onset at the office, at home, not necessarily doing anything rigorous. And they just experienced it. We had one patient who said at a meeting, at a conference,

11:21they collapsed and people just panic because they didn't know. Stroke, heart attack. I mean, the person wasn't grabbing their chest. And their eyes were twitchy. And so one of the things the ER docs had to rule out was seizure. Right. Because they had this post-ictal, socatic movements of the eye. So it was shocking for everyone. And thankfully, there's severe vertigo kind of burned out like many of our patients. It was replaced with dizziness. But thankfully, they haven't had those long durations of vertigo. Did you diagnose yourself? I would think that you would be a pretty good person to figure out. I mean, you had no hearing loss, so it's not manniars. Was it a vestipular migraine? What did you diagnose yourself? I don't want to violate your hip, but if anybody could figure out what was going on, it would be you.

12:23And the short answer is no. I have no idea. I was literally finishing a team's call. The only thing I remember doing maybe slightly different was getting very close to the screen to look at a painting behind one of our attorney's office desks. And as that meeting ended and I took steps away, I was already standing. Started to feel dizziness and I sat down. And it went away after probably 15, 20 seconds. And I got back up. I walked over to another office and felt something similar coming on. Sat down.

13:23Then the third time when I got up, I was like, oh no. Now I had to sit down on the floor and literally have my head on the floor of our office for about an hour and 45 minutes. That's how long it went on. Wow. It was just I remember sweating, feeling nauseous. And then about an hour and a half of dizziness, then kind of felt I can get up now. I moved around on a school chair so I didn't want to walk because I wasn't sure. If it was going to come back and I would fall down. Then I laid down and then had another brief bout that one. The second battle only lasted 20 minutes, but yeah. That one I felt now I was in the bathroom.

14:25Up against the cold tile and I was just like, I tried an Epli maneuver on myself. On yourself. Did you try volume? They tell me that works pretty good. If you had any of that handy. No, and then the second bout resulted. So I tried the Epli maneuver. I couldn't figure out what side may be affected. So I just guessed I had a 50, 50 chance or it. I was tilted my head back in that 45 degree angular motion. And it felt like my head was a 20 pound bowling ball. I was concerned when I did that going, oh, this could be bad. I could hit my head on the tile floor. I'm laughing at you. I'm laughing with you. It was so humbling. I was like, you know, and then I go, okay, 90 second count got it. And then I, you know, rotated it over to be on my belly, 90 second count.

15:25Now I'm supposed to kind of get up. And I was like, oh, I don't know. And that seemed like a tall order. So I just brought myself up against the wall and hung out for another hour. I was able to get up after that and then go home. But yeah, from one 30 to 10 o'clock, was pretty 10 p.m. And the evening was pretty, pretty difficult. But yeah, what surprised me also was how fatigued I felt the next day. You know, yeah, like I had a stain bed most of the day. So that evolutionary system that you described that is incredibly elaborate. Can you let people know how small it is? Like using an object or another part of their body. I've had it described as about the size of your little finger, the nail on your little finger. That it's a pretty small area. That's absolutely right.

16:25The cochlear volume, which is snail shell, we think has about 200 microliters of fluid. So in layperson perspective, that's about four drops from an eyedropper. So it's 120th the volume of an eyeball. So the vestibular system is a little bit more spread out. You have these thin semi-circular canals and we have three. You have these two otolithic organs. I think they may be an equivalent volume across those five sensory organs. But what makes the uterical and sacrile those two otolithic vestibular sensory organs so specialized is that they have these tiny calcium crystals that lie right above the hair cell projections. This doesn't exist anywhere else in the human body. And under a microscope, a scanning electron microscope, you can see these crystals.

17:29And they're the most foreign looking thing. You would never imagine they're part of your body. They look like maybe rough cut diamonds or emeralds, but they're white or at least they appear white under a scanning electron microscope. And we think that creates a micro gravitational environment for which those vestibular hair cells now know your body position in three dimensions. So there's a condition called benign paroxysmal position vertigo, BPPV. And we think in that condition, those otolithic crystals got dislodged. Maybe, you know, from falling off your bike or horse, had some head trauma. And now they're circulating in the semi-circular canals. And they're overstimulating the vestibular hair cells in the semi-circular canals.

18:32So Dr. Eppley, who is a very prominent vestibular physiologist, developed the Eppley maneuver to pool those floating crystals. It's one of the few things that we recommend to people with BPPV. I don't know if that helped, or it was just coincidental that the second attack was shorter. Thankfully, not an hour and a half, but 20 to maybe 30 minutes in duration of then the first attack. And again, nothing since it was just that isolated end of May incident. It happened on a Friday night. Yeah. We'll be right back with more of the Trey Gowdy podcast. The Anduool is now available everywhere in the US. So you can get in on the sports action no matter where you are, including these places.

19:38May this year, most rewarding season ever with Fanduool, age and location restrictions applied, product availability varies by market. CFanduool.com for eligibility, gambling problem called 1-800-Gemma. Is it true that if you experience motion sickness as a child or you have a history of positional vertigo that you may be more likely to have more serious vestibular issues later in life? I don't know. We do suspect that prior otitis media recurrent infections could have some long lasting effects. But those typically involve the outer and middle ear. The inner ear, there are potential infections, labyrinthitis. And that's, I won't say easy to diagnose, but you can image and you can see evidence of inflammation in that area of your skull base where the inner ear lies.

20:41And for your audience, you know, this is deep in the skull base. So I often tell people, take a chopstick and put it through your eyeball. Take a chopstick and put it through your ear where they meet. That's where your cochlea is. So and you're some of my circular canals. So they're deep in the skull base surrounded by the thickest bone in your human body. It's actually the inner ear is kind of sort of near what's left of my brain. Yes, it is very close to your brain stem. The eighth cranial nerve, the vestibular cochlear nerve comes together and then separates entering your brain stem. Occasionally, there can be a tumor that grows on the nerve. It used to be called an acoustic neuroma. Now it's called a estibular schwannoma, which is more appropriate.

21:43It grows from the glial cells that ensure the vestibular nerve. And as it gets bigger and depending on its location in the internal ear canal, it may be surgically approachable from one of four ways. Sometimes people will use radiation, a gamma knife to oblate it. Thankfully, they're rare. Sometimes there are larger tumors involving the nerve neurofibromatosis type two tumors that can actually take the entire nerve and even part of the brain stem. And what's amazing is that there are auditory brains to implants that can help those patients, which I never thought was possible. When you see the deficits that were caused by that tumor and the rule of that tumor.

22:44So there have been a lot of advances from an engineering standpoint, hearing aids, middle ear implants, cochlear implants, auditory brain implants, brain stem implants. But we haven't had such a series of success with medications or drugs. In fact, just the opposite. We know a lot of medications are highly auto toxic. They cause hearing loss and dizziness. Cancer chemotherapies, certain types of antibiotics, certain types of diuretics. Those are the three major classes. But now there's growing evidence that even a lot of these biologics, these recombinant growth factors may have a significant auto toxic, as we call it, side effect. More broad, you know, it can be hearing loss, it can be tinnitus, dizziness or vertigo. Sometimes the side effects of these medications are subtle.

23:46A patient may describe a little bit of ringing buzzing, clicking, and it was temporary. Or maybe a slight difficulty in hearing conversations that they didn't strain to hear before. And then it's temporary. But, you know, those insults, you know, those accumulate. And over time with aging, they can become progressive. In fact, in animal studies, we use chemotherapies, we use antibiotics, we use high-dose diuretics to cause hearing loss. And a couple of those experiments, we've translated into successful human studies. And one we're about to publish. So it's very exciting. So you and I have a mutual friend named Dr. Habib Rizik at MUSC in Charleston, South Carolina. And I remember the first time he told me, because I do have friends that complain about tinnitus, which show you how dumb I am.

24:55I used to think it was pronounced tinnitus, but tinnitus is really the absence of sound. There is no sound. Even though it sounds like a freight train is in your head or a tornado, it is fannum. It's not really a sound. It's the perception of sound in the absence of sound, in the absence of an environmental stimulus. Yes. So what's amazing about it is much of it is due to noise. So intense noise can cause hearing loss, a loss of hearing sensitivity. It can cause an apparent gain of function hearing sounds into the absence of sound. And then for a small subset, patients describe hyperacusis, where normal sounds are bothersome to them. And some of the descriptions are horrific. Some of these patients will describe like a bomb going off in their head if they get subjected to a police siren or the backfire of a car.

26:07Some unanticipated sound for this reason, a lot of patients that have hyperacusis don't go outside. They're fearful. A dog barking can set them off. A normal sound that we wouldn't consider, you know, painful. They have this autonomic response to. It's quite amazing. But yes, the complexity of tinnitus. And you're right. There are two camps, tinnitus or tinnitus. I always thought it was our colleagues in the UK across the pond. And there are always debates is tinnitus a peripheral disorder or central. And I think to be fair, it's both. Most people would agree that the majority of tinnitus is due to what we call deaffrontation. Meaning there was some peripheral injury to your auditory hair cells or structures within the cochlea that thing, you know, unfortunately resulted in changes in the brain.

27:13Maladaptive plasticity. So now there is a gain of function. So people have made some correlates to phantom limb pain. But it isn't necessarily pain. It's a perception of sound in the absence of sound. And there are rather simple sounds. There is some complexity to it. And there are a small subset of patients who can modulate the pitch of their tinnitus by recruiting other sensory motor functions, clenching their jaw. It's very interesting. And again, further supports this maladaptive plasticity. So we know the brain is very plastic. We know there's ongoing neurogenesis, the making of more neurons and glia. It does turn down an aging. But the cochlea and the vestibular system are somewhat hardwired at birth. In fact, we know we start hearing in utero.

28:17And we can discriminate speech clearly, an infant. And just after birth can sometimes even orient to their mother's voice. Wow. I know. And when our first child was born, the nurse said to my wife, call out his name. And he opened his eyes. And there was a not quite a head turn. They can't turn their head. But we were like blown away. Like, whoa, you know, as you know, when they're born, they're not that reactive other than crying. No, I think they do. They still get the app guard test. I think I barely passed that. I was a pediatrician. He said I had to cheat on some girl in the nursery's paper to pass the app guard. All right. So I come to you and I got shingles. If you're a dermatologist, that's not that complicated. You got me diagnosed. I come to you with a fracture. You can see it on an X ray.

29:18I come to you and tell you that I'm a little bit off. I'm dizzy. Maybe I have the symptoms you had a vertigo accompanied by physical illness. There is so much overlap between triple PD, the stipular migraine, the years. How do you figure out what someone has? Well, that's really the job for happy Brizic, one of the world's experts on vestibular disease. So he's double boarded highly specialized. And there are a series of tests that we do. Nothing's considered the gold standard. And you've probably had some of these tests done. Warm and cold water caloric. And no one wants that done again because it can make you feel delicious. Yeah. You had some vestibular of oak myogenic potential. See Vemps, cervical and ovums, ocular. So we now start to look at the vestibular system's response to stimuli, acoustic temperature.

30:27Oftentimes you have to rule other things out, like tumor. Sometimes it's a bony malformation of the inner ear. That is rare, but it is present. So a lot of ruling out some ruling in with manures disease, the disease classification changed about 10 years ago. 30 years ago, using the 1995 criteria, you had to have severe vertigo lasting at least 20 minutes in duration. Not one, not five, not 10, 20, and two times. And then in 2015, they allowed for dizziness, not just vertigo. And they also put upper limits on the vertigo and dizziness. And then for definite manures, you have to have low frequency hearing loss in your affected ear, dumb, documented by audiometry.

31:30And of course, the other classic characteristics of tinnitus and oral fullness or pressure. So many of our patients with unilateral manures, and again, two thirds or more, have one side that's affected. We don't know why. And after three to five years of manures disease, the severe vertigo attacks wane. We don't know why. Some people think it's due to medical management, but the outcomes research really don't support that. And of course, nothing's FDA approved. It can be replaced by dizziness, but a lot of our patients who are five to 10 years into their disease, they'll have what they think are disease-free periods or symptom-free periods within one day they'll wake up, but have more pressure on their affected side. They'll have more ringing in the affected side. And when they walk to the bathroom, they'll say, I felt a little unsteady.

32:35Sometimes patients they'll suffocate, they'll take a mechalazine, acidating an eye histamine, that was approved for motion sickness, or they'll take a bow. And they feel this can help them weather the storm, so it doesn't go into full-blownen years. And then finally, after 10 to 15 years, this is when people can become by lab. So the quote unquote unaffected, the good ear went bad. And that's unfortunate. So we've enrolled all types of patients from the classic unilateral to the delayed phenotype. These tend to be over patients late 50s or early 60s, where they first noted the auditory symptoms, the hearing loss, the timidus, the pressure. In fact, some of them don't have a severe dizziness or vertigo episode until months later. And then they're ruled in after ruling out other diseases.

33:39So just because you have vertigo doesn't mean you have min years. You know, again, 30 years ago we would say min years was a disease of vertigo. Now I think it's an auditory, very complex auditory, the stibular disorder that starts out unilateral, can go bilateral. Unfortunately, the majority of patients progressed to severe hearing loss, some have become deaf. Some have received cochlear implants now on their affected side because cochlear implants were expanded in their indication about 70 years ago to single-side deafness. So we've enrolled at least three to four types of min years patients. Younger, older, one side, both sides, vertigo, dizziness dominant to hearing loss, tinnitus dominant. But we all agree that most patients will progress to severe hearing loss and some level of intractable tinnitus where it's now a chronic, chronic disease.

34:51All right, I want to move to some good news if possible, although I may take a roundabout way to get there. So I suspect one of the first questions, the treating physicians of the world like Rizic and McCracken and others. They ask, are you depressed because your whole life has changed? You can't hear as well anymore. You're worried about losing your job. You can't mean your balance is shot all the Hades. And you do tend to kind of lose hope, which then sends them to the internet. And you see that there hadn't been all that much new stuff offered. I mean beta-hystine, which you got to get from a compounding pharmacy in the US, low sodium diuretics, you get mixed views on that. And then up comes something called sound pharmaceutical with SPI, 1,000 and five. And that is the hope that people have been waiting for. So walk us through SP, I call it SP, 1,000 and five. I think it's SPI, 1,000 and five. You would know better than I do. So as you came up with it, what is it?

36:06What does it do? And where is it in the process? Yeah, so thank you for that recap because a lot of our patients that email me, call me and unfortunately I can't respond, but to a fraction of them daily calls, daily emails from essentially all continents. SPI, 1,000, five is an oral drug. It's in a capsule. So the capsule is called SPI, 1,000, five. It's 200 milligrams of a new chemical entity, a drug that has never been approved before called Epsilon. Epsilon has been highly researched by others and sound. We focused on its ability to prevent and treat various forms of hearing loss and tinnitus. In upwards of 1,000 plus animal studies, mice, rats, guinea pigs, and now almost 1,000 enrolled patients across five different indications.

37:06Our most advanced is min years disease. And we've received breakthrough therapy designation, a first for min years disease, a first for a drug to treat a hearing loss or tinnitus disorder that's acquired. And it's working very well to improve the low frequency hearing loss that's critical for the min years diagnosis. We have strong evidence in tinnitus and after prolonged treatment in an open label extension study where patients from our phase three randomized double blind placebo controlled study could go on to receive active treatment for up to 12 months. We see continued benefit durable effects and we know that disease progression, in patients that we've enrolled who are in their late 50s on average with a 9 to 10 year duration of disease before they started our study.

38:10Don't typically get better. They hope to just remain steady eddy. But we've seen durable improvements from baseline 15 months later. So we think hopefully next year we'll get the first drug approved for the treatment of min years disease, the first drug to treat an acquired sensor in a hearing loss or tinnitus disorder. It's very promising. In fact, when we started sound pharmaceuticals 24 years ago, I had not envisioned in our wildest dreams that this would be helpful in min years disease. We were studying things that we could model pre clinically in animal studies that we knew caused hearing loss and tinnitus and that was noise. That was auto toxic drugs, cisplatin chemotherapies, amino glycoside antibiotics.

39:12And again, we've done hundreds if not thousands of animal studies now. And a lot of that work has been published is being published. And so those were our first steps to clinic. And during the publication of one of our animal studies, where we looked at the cochlea of these animals within hours of an intense noise exposure, typically we would expose them intense noise and reassess their auditory function over time and then sacrifice them weeks or months later. We never sacrificed the animals within hours of the exposure, but what was clear is our drug was helping not only in what we call the permanent threshold shift or chronic period, but in the acute period. And we didn't think a drug could do that. We thought some of those changes in the cochlea were more. Well, they were sensory neural, but involved more mechanical elements. But when we did, we saw evidence that looked like manures disease, a swelling of the cochlear dot.

40:23As you know, manures diseases often called idiopathic and alabatic hydrops. In fact, there is a code for something called cochlear hydrops or what clinicians will say is cochlearman years. And I remember when I first learned about that 30 plus years ago, I was like, wait a minute, I thought mean years was a disease of vertigo. What is cochlear hydrops and what's cochlearman years? And again, more of our European and Asian colleagues tend to use that diagnoses, although I know there are some neurotologists that say, yeah, they look like a manures year, but they don't have vertigo or dizziness. So, you know, and again, to add more complexity to manures, there is this proportion typically an older adult late 50s or early 60s that has that delayed manures phenotype where they presented like a cochlear manures.

41:25And then 6, 12, 18 months later, had a big attack of vertigo or certainly dizziness. And you know, again, I think it was a big shift in a credit to a lot of the otologist, neuro-otologist, for saying, probable manures disease should allow for dizziness. I think so many patients before, you know, neuro-otologists were, you know, very rigorous until you've had severe vertigo, I can't rule you in from a nearest disease. But they were dizzy, at least they reported dizziness. Yeah, our drug helps repair those injured sensory structures, hair cells, supporting cells, cells called the Stray of Ascalarus, or cells within the Stray of Ascalarus that make the ionic environment that allows hair cells to work correctly or to polarize correctly, and even the auditory nerve.

42:25So we chose an enzyme target that is highly expressed in the inner ear, that when you knock that gene out in mice, those mice are deficient in their ability to kind of self repair, they're hearing after intense noise, autotoxic drugs, aging. So we think we have one of the first validated drug targets. It's called Glutathion Proxidase I, and GPX I is, again, highly expressed in the cochlea, it's highly expressed in areas of the brain that control behavior and some executive function, then lunging kidney. So we think we have broad applicability, even beyond the inner ear, and we've seen great evidence that it is kidney protective, and that's something that we're publishing on our first auto toxicity clinical trial.

43:27We weren't anticipating that it would be that, as we call it, nephroprotective or kidney protective, and that specific patient population, they were receiving an auto toxic antibiotic that is we know causes hearing loss, tinnitus, and injury to the kidney. We thought because these patients were only being treated for two weeks with this antibiotic, there would be no kidney injury. And there was an our drug prevented that, so we were really excited by that. That was an unanticipated finding. All right. So two part question. One's a theory or one's practical. I used to play a lot of golf. My wife would tell you I still do, but I'll go try a putter. And if it didn't work within three or four strokes, I either break it over my knee or go back and trade it bypass golf. I have no patients whatsoever.

44:28Zero. How long did it take you to come up with this? And are you ever tempted to give up? I heard the early 2000s. That to me seems like a lifetime. Yeah, next next year if we get this drug approved, it will be 25 years in the making a quarter century patients to wait 25 years to see if something works. That's a different skill set. Well, thank you for that. Because of this, I've never really taken up golf. I'd probably break every potter, every driver, taking up volume or nothing. You know, in some respects, I don't have the patients for golf. But you can wait 25 years to see if absolutely helps. Well, we know it helps on that I'm convinced of to get the first drug approval. I didn't think it would take this long. You know, I was very naive when I left academics. In fact, I'm not licensed. I'm not board certified. I left my training early because I worked in three different hospitals, actually four.

45:41And two of which I saw a fair number of patients, even in my medical rotations. And invariably, people didn't want to get a hearing aid. But a typical presentation would be a 40 year old post military post construction, mining forestry, some noisy occupation, or they've lost a lot of hearing. And he said, don't you have a pill for me, talk. I don't want to get a hearing aid. My grandfather had a hearing aid and no one spoke to him. And it was amazing. You know, I was recollecting this event that an elder, not elderly. That's too strong. A person over 50. Also, remember in the vice presidential debates in 91, 92, Al Gore, Admiral Stockdale.

46:48And they asked Admiral Stockdale a question. And he asked them to repeat the question because he had his hearing aids. And there was a gasp, an audible gasp from the audience of, oh my gosh, he's so old he needs hearing aids. And you would never have said that if someone said, hey, I want you to read this passage. And they go, you know, you could make a joke. I ending my glasses on blind is about. And people would laugh. Not gasp. And so a lot of people don't want them because of the stigma. And I think it's still industry standard for patients to delay getting fitted for a hearing aid by almost a decade. Then when they get them, they pay a lot of money out of pocket. And they often don't wear them routinely. And there are a lot of reasons for that. But I was amazed how many men actually don't want to appear with hearing aids socially.

47:52And is it the stigma because they don't want to be perceived as being older or elderly? I wouldn't say they're frail, but, you know, each person has their own self perception. But I was amazed by this. So many veterans, you know, no, they had, and oftentimes their spouse was the better hearing partner. And when act as a surrogate, they would be there. And they would be lobbying for their husband to be fitted for hearing aid. And because, you know, it's affecting their lives, their social lives, you know, he's not picking up on everything at dinner. He's getting frustrated. He doesn't know why people are laughing. And, you know, I have to whisper to the TV is very loud. No one wants to sit with dad and watch, you know, something because, you know, he has to have it very high.

48:53And then, of course, now with so many children, young adults being exposed to loud sounds through iPhones, iPods, any device that they listen to eight hours a day, that can culminate into significant noise and deuterium loss. So one of our first proof of concepts actually kept into that. We went to one of my colleagues at the, at that time at the University of Florida, Colleen LaPrile. And she had developed a personal music player protocol. We ended up calling it the calibrated sound challenge. So prerecorded soundtracks four hours, you couldn't adjust the intensity or duration. And because it was placed with insert earphones under an audiologist point of view, it overcame a lot of the variability that the FDA wanted us to control for.

49:55So young adults with no hearing loss, no tinnitus were randomized placebo control double blinded three different active groups. Because we could plan the experiment, essentially, we could start dosing those young adults two days before it takes about two days for our drug to get to what's called steady state. And then we continued them through the day of that exposure and the day after. And it worked very well to prevent the temporary noise and deuterium loss. So we dialed in a level of sound that we thought was OSHA acceptable would only create this very temporary slight threshold shift or hearing loss that resolved in 24 hours. So the goal was to prevent the shift and it did in about half the subjects, which was remarkable. Yeah, it was, it was significant with a very small sample size. We ended up publishing it in the Lancet as an 11 page primary research article. And we're looking to extend those results next year and an active duty military population.

51:04And collaborating with Walter Reed and then ultimately age related hearing loss and chronic tinnitus in the VA population. So we've been kind of unofficially collaborating with the VA. I've been a little bit of an advisor to them, as well as Department of Defense. And now we want to become more directly collaborative with this oral drug right now. It's taken twice daily. We have pretty good safety across a variety of patients. We don't think there are any drug drug interactions, which is something you always have to be concerned about. And yeah, I was just, well, it's nice to see your preclinical work in these lab models of disease translate to human clinical trials. That's where a lot of things don't translate. And you can kind of see it now preclinically and how the scientists did their experiments, how they gave the drug when they gave the drug, whether they're model is too specific.

52:15And sometimes there's a good and bad about if it's too specific, then it probably won't translate broadly. You're going to have to find a very, very, very specific disease or form of hearing loss and tinnitus due to one specific ideology. But there has been some success in our field recently, the FDA through the commissioners national priority voucher approved an ultra rare form of genetic deafness. Actually, the condition is called auditory neuropathy. And these children are born hearing impaired, some may, you know, have almost complete hearing loss. There can be a symmetry between the ears, so they're not exactly duplicative and how they look. But their genetic variation results in a missing protein. And this protein is critical for synchronized activity at the level of the hair cell and the nerve.

53:19So they haven't lost many cells yet. This is very unusual. And you can do a test called auto acoustic amishes and measure hair cell activity. It's not a hearing test, but measure hair cell activity and say, hey, if they have this, then we can infer that you haven't lost a lot of cells yet. You have the basic structure of the sensory organ in the cochlea. And so they use that test to enroll these patients that had these genetic variants in auto furlund. So this was remarkable. The company received a voucher in October of last year. And it was approved conditionally in April of this year. And conditionally because the open label, no placebo compared to control, the open label study that got them approved, it's still ongoing. It was approved based on 16 of 21 injected children.

54:19We'll be right back with more of the Trey Gowdy podcast. Fandool is now available everywhere in the US. So you can get in on the sports action no matter where you are, including these places. May this year, most rewarding season ever with Fandool. Age and location restrictions apply. Product availability varies by market. CFandool.com for eligibility. Gambling problem called 1-800-Gemma. So Kyle Diomatis is the acting FDA commissioner of head and as a guest on my show, he is trained as a lawyer like I am and not an ENT. But if he were listening or if you were having a conversation with the commissioner about SPI-105, you've already, like, you've been through stage one, passed it.

55:23I think you're in stage three now or are you out of stage three? Now we completed our pivotal phase three study. We hit our co-primary endpoints. We've received not only fast track, but breakthrough therapy designation. So two of the four expedited programs. The CNPV is very interesting in that it can further expedite this program. So the example that I gave with the Otoferlin gene therapy approach for this ultra-reform had also received fast track designation, not breakthrough. Well, because the phase one, too, is still ongoing. So it was elevated. And because of this was approved in record time. I don't know of another gene therapy study that was approved based on an ongoing initial phase one, too. That won't be completed until 2032.

56:26But and these children who are born with this ultra rare variant that affects maybe 25 to 45 children in the US are serviced by cochlear implants. So there is an approved treatment plan for them for something like maynyars disease where no one's been successful. And we've, I think it's fair to say we've been the most successful. We've certainly enrolled the most patients, almost 600 now. We've again completed a phase three pivotal study with co-primary endpoints. But when you're the first, sometimes it's difficult for a regulator like the FDA to say, okay, what's the improvable endpoint? What's the duration of treatment? You know, all of our work has been placebo-compared and we've achieved statistical significance there using, well, we would agree clinically relevant endpoints.

57:27So we did apply for a commissioners national priority voucher and four months ago and we were selected to present at the FDA's town hall meeting in June. So, you know, hopefully, you know, we'd be happy to talk with the FDA at any point about why we think we should qualify. Because we have a new chemical entity, a new chemistry that's never been approved. So our drug Epsilon contains Selenium that mimics the activity of glutathione peroxidase one, which is a critical Seleno protein. The FDA has never approved a drug with Selenium in it. We've achieved some additional assessments to show safety and control for what we think is a very pure form of Epsilon without Selenium in pureities. And in a new therapeutic area, so you have a new chemistry and a new therapy at a gary that has never received approval before.

58:35So it's the trifecta of difficulty and probably why it's taking a quarter century or almost a quarter century to get to this point. I thought, again, not necessarily a manures disease, but acute noise-induced sharing loss or acute odor toxicity that we would have a drug approval by now. Right. I'm going to act like a pro bono lawyer for a second. How many continents have you heard from people that suffer from the years? Is there one you haven't heard from? Maybe an article? No, no, you know, five of the seven. I have no one from the Arctic Circle or Antarctica, but no, throughout the Asian subcontinent at areas of Africa. Obviously, the US, Asia, a lot from India now. Very compelling stories. You know, it's difficult. Sometimes I'm just overwhelmed by the outreach. In the early days, I could respond to the majority of people 20 years ago.

59:48Now I can't. It would just consume all my time. Well, we don't want your time to respond to emails. We want your time getting it approved. So five of seven continents, the five that happen to be inhabited by human beings. Probably all 50 states, if my math is correct, I suspect someone from every state suffers from the years. Folks are losing their job, particularly if you have bilateral minors, I don't know how they keep their job. They're losing hope and there is a drug that is the brightest star in the constellation. And well, forever since Prosper minors, I guess, either had the disease or named it. I'm not sure which. I don't know if he had it or if he named it, but there are some old French. Okay, Prosper minors. 25 years, you've been working on it and you're very, very, very close.

1:00:50You've already received some favorable treatment from the FDA, but there's more they could do. And you're willing to go make the pitch and be cross examined. If they have questions about, I mean, well, the research speaks for itself. You're at some of the best teaching hospitals in the world or where your studies are. Yes. And you know, that's what both led us to MUSC in Charleston, South Carolina. They have had for about 25 plus years, one of the leading otolaryngology departments in the country in the world. And in fact, when I was an MD PhD at the University of Virginia, the head of otology, neuro otology there Paul Lambert was vice chairman. And I left. I went to the University of Washington to do my research fellowship that was NIH funded.

1:01:52And many respects that gave rise to a lot of these ideas that have developed into drugs at sound form, but Dr Lambert in 1999 moved to MUSC in Charleston. And at that time, in many respects, that would have been considered a step down. Right. They only had four full time faculty. Their residency program was on probation. I think they only had two residents at the time. And he added 20 full time faculty. They have grown one of the strongest, deepest neuro otology programs. They have one of those 26 boarded fellowships. They have five world class neuro otologists. They're relatively new chairman that replaced Dr Lambert. Robert Labadi is quite accomplished has a engineering background and does a lot of work involved in cochlear implants.

1:03:01And he came out out of Vanderbilt and it turned out until about three years ago or four years ago at a dinner with Dr. Rizic, I didn't realize he was Paul Lambert's last neuro otology fellow. Oh, great. Yeah. It was amazing. After our phase two results at the end of 1999, sorry, 2019, we convened most of the investigators to help design a phase three protocol that we were going to submit to the FDA and start trials in 2020. Obviously, COVID delayed the start of that. But a lot of the people around the table and I thought I knew how long I had been colleagues with friends with them. And then I looked at Paul and I was like, oh my gosh, I met you in 1992. I transferred down from Georgetown Medical Center as an MD PhD.

1:04:05And on the weekends, he was doing research in mouse models of hair cell regeneration. What I didn't realize was how many people around that table have been his research, not research, but neuro otology research fellowships. One of our colleagues at Georgetown was, I trained in Paul. It was like, it was amazing how one person could really set MUSC on this incredible path. And so there, I think a top 10 NIH funded center, they have a top, again, cadre of neuro otologists that you had mentioned. Yes, Teddy McCracken, Ted Meyer, they have some new other neuro otologists I don't know as well.

1:05:06But what makes them highly prolific in clinical trials is Dr. Sean Wynn and he's become a close friend. And to Paul Lambert's credit, he hired him and said, we want to do translational research, we want to do clinical trials. And sometimes you need that kind of leadership to get things going. And there's highly prolific. They do more systematic reviews and meta analyses. We cite a lot of their work. And what makes minors even more complicated is what we call the placebo rate. And so MUSC under Dr. Wynn did the first and I think only published meta analysis of the placebo rates in all minors trials that they could evaluate. And vestibular severity or vertigo severity had the highest placebo rate.

1:06:11It was over 50%. Because again, we can't objectively measure it. We often don't see it in clinic. A patient reports this and we do believe them. Or we see them afterwards and we see some of these changes in their eye movements. But now the lowest I think core symptom, meaning lowest placebo rate of a core symptom was hearing loss. Because that's measured by an audiologist. Obviously it does depend on the patient responding. But that's more of an objective measure. It's one of the few that we can do other than imaging. And that test that I, if I were still in Congress, I would have banned, which is in noise. Gosh, if I have another words in noise test, I don't know what I'm going to do. That's why I have my wife is to tell me what the person said.

1:07:13We're at a cocktail party. So I don't know if they're telling me they lost their job or won the lottery. If there's noise, I have no idea what they just told me. And I know a lot of men who say, I don't want to go to that big fundraiser, Gell, it's so loud. I'm shouting across the table of 10 people. And after a while, if you watch their body language, they kind of just pull back. They look like they're bored, but they're straining to hear. In fact, this is something that's been documented. And is potentially an endpoint for certain types of people affected by hearing loss. And that is fatigue. They're straining to hear. And you'll hear people literally talk about feeling wiped out after going to a big conference and talking with dozens of people in a noisy, complex environment.

1:08:15And saying, I need a now after that. You've had some fluorescent lights or strobe lights to it. And that is a glimpse of Hades. But the good news is for the folks that have the stipular disorders many years. And there are other indications as well. There could very well be a light at the end of the tunnel. And it may be called SBI-105. Yes. It's been a long time coming, but we have good results. They're not perfect results, which actually makes me believe them more. In our acute noise study, even though it was so well controlled, right? One sound source, one intensity, one duration. Medical insert earphones under an audiologist's supervision. There was asymmetry between the ears. Not every frequency shifted the most at every time.

1:09:17So it was literally noisy. And even in that closed environment, we had something that I thought was environmentally relevant. So we are... We learned so much from our patients, our tests. And then one of the things we like to do at sound is when we learn from our patients during these clinical trials, as we go back into the lab. And try to incorporate some of that. We've done that with cisplatin. We've done that with... I mean, a glycoside anabolic. We've changed the way we've given the dose... The dose schedule to better mimic what was clinically relevant. So we've learned a lot from working with clinicians. And it's really amazing. And I think we've had a great learning experience working with top academics. And some private doctors as well.

1:10:17We have some past presidents of the Academy of Ode to Learn Dolly. Past presidents of the American Ode to Logic Society. American neuro-odologic society. We go to these meetings where... Societies you'd never heard of. Come. And it's amazing to see everyone's commitment to the patient. You know, all that training. You know, it's just amazing. One of our colleagues at UT Southwestern, when she found out we were in Seattle, Washington. She goes, I wasn't Seattle, Washington. You were? Yeah, I was there for 15 years. We loved it. I go, oh, you did undergrad there? No. I did my undergrad at Berkeley. I go, okay. I was an MD-PhD for nine years. She did the six-year ENT residency. And then she went back east to do her fellowship.

1:11:17So I was like, well, yeah. Most of my colleagues, especially some of my closest friends who are, you know, key opinion leaders in this field, trained as MD-PhDs. And in some respects, in rival labs, in the early 90s, that were trying to find a way to regenerate auditory hair cells. And they're quite accomplished. One in particular, Heinrich Stekker, who's at University of Kansas. Did the world's first gene therapy job? And as, you know, really pioneered therapeutic delivery and access to the inner ear. So just, you know, kind of this lifelong journey. So it's some, you, as I say, at Sound, we're gluttons for punishment. We'll do the try to do the unimaginable.

1:12:18You know, we've had some investors in the early days. See, Dr. Kiel, we know you're credible, but we can't get our heads around this. How's a drug, an oral drug, going to help prevent noise induced hearing loss or auto-toxicity? Maybe they thought auto-toxicity, you know, if you bind up the platinum, we could see that. But that may be counterproductive. And then literally a couple of them said, we can't get our heads around this. And as it turns out, they're no longer in the venture capital business. Yeah, but you're still around. And on the cusp of something, I'm going to send a copy of this podcast. We'll make sure the commissioner gets it. I know he's interested. And I'll make sure Rizad gets it since we mentioned his name multiple times. But I cannot thank you enough. Speaking of fatigue, the thought of going to get an MD and a PhD made me tired just hearing you say it.

1:13:22I can't imagine going to school that long. But for those that suffer from hearing loss or vertigo or tenidus, I am sure that they are expressing their gratitude to you right now because it does change to their lives. And what they're looking for is a little bit of hope that maybe things won't get worse and possibly even get better. Now, if we could have that impact, it's, it's aren't been rewarding. I mean, as you said, I get some lovely notes, emails where people just thank us for, you know, dedicating our lives to this. So, yeah, it'll be great one day when, yeah, I can say to that 40 year old, well, we may have a drug for you. And hopefully it can keep you hearing better longer. It's possible you may not need a hearing aid, but hearing aids aren't bad things.

1:14:22And what's terrible is are those patients that got the hearing aid and now they're beyond hearing aids. That's, that's, that's difficult. But thank you again for this attention, Trey. Yes, sir, it will continue because I got a lot of people that I know and care about that have the stipular disorders, including many years. So thank you, and I know I'll be talking to you again soon in the, in the meantime. Thank you, everybody, for joining us today and Dr. Thank you for your time and for your research. Thank you very much. Listen, add free with a Fox News podcast plus subscription on Apple Podcasts. And Amazon Prime members can listen to this show, add free on the Amazon Music. Van Dool is now available everywhere in the US. So you can get in on the sports action no matter where you are, including these places.

1:15:30May this year, most rewarding season ever with Fandool, agent location restrictions apply, product availability varies by market. CFandool.com for eligibility, gambling problem called 1-800-Gemmar.